Abstract
Epithelial ovarian cancer (EOC) is the most deadly gynaecologic malignancy due to late onset of symptoms and propensity towards drug resistance. Epithelial-mesenchymal transition (EMT) has been linked to the development of chemoresistance in other cancers, yet little is known regarding its role in EOC. In this study, we sought to determine the role of the transcription factor TWIST1, a master regulator of EMT, on cisplatin resistance in an EOC model. We created two Ovcar8-derived cell lines that differed only in their TWIST1 expression. TWIST1 expression led to increased tumour engraftment in mice, as well as cisplatin resistance in vitro. RNA sequencing analysis revealed that TWIST1 expression resulted in upregulation of GAS6 and L1CAM and downregulation of HMGA2. Knockdown studies of these genes demonstrated that loss of GAS6 or L1CAM sensitized cells to cisplatin, but that loss of HMGA2 did not give rise to chemoresistance. TWIST1, in part via GAS6 and L1CAM, led to higher expression and activation of Akt upon cisplatin treatment, and inhibition of Akt activation sensitized cells to cisplatin. These results suggest TWIST1- and EMT-driven increase in Akt activation, and thus tumour cell proliferation, as a potential mechanism of drug resistance in EOC.
Highlights
Epithelial ovarian cancer (EOC) is the most deadly gynaecologic malignancy due to late onset of symptoms and propensity towards drug resistance
The related transcription factor TWIST2 has been shown to lead to platinum resistance via Akt activation in another EOC model, but whether TWIST1 can function in the same manner is unknown[22]
Parental Ov8GFP cells express an intermediate level of TWIST1, an empty pCI-Neo vector resulted in intermediate TWIST1 expression, showing no substantial effect on TWIST1 from transfection alone (Fig. S1a,b)
Summary
Epithelial ovarian cancer (EOC) is the most deadly gynaecologic malignancy due to late onset of symptoms and propensity towards drug resistance. We sought to determine the role of the transcription factor TWIST1, a master regulator of EMT, on cisplatin resistance in an EOC model. TWIST1, in part via GAS6 and L1CAM, led to higher expression and activation of Akt upon cisplatin treatment, and inhibition of Akt activation sensitized cells to cisplatin These results suggest TWIST1- and EMT-driven increase in Akt activation, and tumour cell proliferation, as a potential mechanism of drug resistance in EOC. This study is the first to focus on the specific mechanisms by which TWIST1 confers cisplatin drug resistance in ovarian cancer, a novel function for a transcription factor that has previously primarily been only associated with tumour cell motility. Connecting TWIST1 and the EMT process as a whole to the dual malignant functions of increased cancerous cell proliferation and drug resistance makes it an especially attractive target for aggressive, drug-resistant carcinomas that require a combination of therapeutic approaches
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